Geneviève Bernard - Academia.edu (original) (raw)

Papers by Geneviève Bernard

Human Genetics and Genomics Advances, 2021

Biallelic pathogenic variants in LSM7 impair assembly of LSM complexes, impairs neurodevelopment ... more Biallelic pathogenic variants in LSM7 impair assembly of LSM complexes, impairs neurodevelopment in zebrafish and may be associated with an ultra rare neurodevelopmental and neurodegenerative disorder

Archives of Neurology, 2012

To report a novel clinical and genetic presentation of a patient with 4H syndrome, which is a rec... more To report a novel clinical and genetic presentation of a patient with 4H syndrome, which is a recently described leukodystrophy syndrome characterized by ataxia, hypomyelination, hypodontia, and hypogonadotropic hypogonadism.

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2019

Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-... more Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, inclu...

The American Journal of Human Genetics, 2021

POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in ... more POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy. We describe six unrelated individuals with de novo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.

Neurology Genetics, 2020

Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the ar... more Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Molecular Genetics & Genomic Medicine, 2019

This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Movement Disorders Clinical Practice, 2018

Objectives Objectives: To identify the prevalence of dystonia in a RNA Polymerase III (POLR3)-rel... more Objectives Objectives: To identify the prevalence of dystonia in a RNA Polymerase III (POLR3)-related leukodystrophy patient cohort and to further characterize their dystonic features. Background Background: POLR3-related leukodystrophy is a hypomyelinating leukodystrophy characterized by neurological and non-neurological features. Dystonia remains a challenging and under-recognized feature. Methods Methods: A retrospective chart review was performed in a cohort of 20 patients for whom videos of a standardized neurological examination were available. Patients were recruited at the Montreal Children's Hospital of the McGill University Health Center and the Myelin Disorders Bioregistry Project. Families were consented at the initial assessment and the following data was recorded: age and symptoms at clinical presentation, investigations, causal gene and mutation(s), type and severity of dystonia, and treatment response when needed. Standardized examination videos were reviewed by three independent reviewers and scored using the Global Dystonia Scale. Results Results: 10 males and 10 females were included in this study; 12/20 had POLR3A mutations, while 8/20 had POLR3B mutations; 19/20 patients had documented dystonia, with 3/19 requiring therapy. There was a good response in two patients to a single agent, and a poor response in one patient to three agents; the majority had mild-to-moderate multifocal dystonia without a functional impact. Conclusions Conclusions: Dystonia is a common, yet underdiagnosed, slowly progressive manifestation of POLR3-related leukodystrophy, and in most cases has limited-to-no functional impact. When treatment is needed, good response to typically used medication may occur. Further studies are needed to assess evolution of dystonia over time, patients' functional outcome, and response to therapy (when needed).

Tremor and other hyperkinetic movements (New York, N.Y.), 2017

The movement disorder of brain-lung-thyroid syndrome can be responsive to methylphenidate.

Brain : a journal of neurology, Dec 20, 2016

We conducted a genome-wide association study of essential tremor, a common movement disorder char... more We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quan...

Case reports in endocrinology, 2015

Introduction. 4H leukodystrophy is an autosomal recessive RNA polymerase III-related leukodystrop... more Introduction. 4H leukodystrophy is an autosomal recessive RNA polymerase III-related leukodystrophy, characterized by hypomyelination, with or without hypodontia (or other dental abnormalities) and hypogonadotropic hypogonadism. Case Presentation. We describe a 28-year-old female who presented with primary amenorrhea at the age of 19. She had a history of very mild neurological and dental abnormalities. She was found to have hypogonadotropic hypogonadism, and magnetic resonance imaging of the brain showed hypomyelination. The diagnosis of 4H leukodystrophy was made. She was subsequently found to have mutations in the POLR3B gene, which encodes the second largest subunit of RNA polymerase III. She wished to become pregnant and failed to respond to pulsatile GnRH but achieved normal follicular growth and ovulation with subcutaneous gonadotropin therapy. Discussion. Patients with 4H leukodystrophy may initially present with hypogonadotropic hypogonadism, particularly if neurological an...

Movement Disorders, 2012

share the same well-defined neurological picture, characterized by onset in the late second or ea... more share the same well-defined neurological picture, characterized by onset in the late second or early third decade of life with a progressive, disabling, and drug-resistant action myoclonus and an invariably fatal course. The diagnosis is challenging until the full clinical picture is present. Progressive myoclonus ataxia or epilepsy with SCARB2 mutations should be distinguished from Unverricht-Lundborg disease, myoclonic epilepsy with ragged-red fibers, Lafora body disease, the neuronal ceroid lipofuscinosis, sialidosis, dentatorubro-pallido-luysian atrophy, 7 and myoclonus dystonia syndrome (DYT 11). Legends to the Video Video. The video shows the severe postural and intention myoclonus.

Journal of Neurophysiology, 2007

In the cat, section of all cutaneous nerves of the hindfeet except the tibial (Tib) nerve supplyi... more In the cat, section of all cutaneous nerves of the hindfeet except the tibial (Tib) nerve supplying the plantar surface results in a long-lasting decrease in the intensity of Tib stimulation needed for a threshold response in flexor muscles and an increase in the amplitude of the phase-dependent responses recorded in various muscles during locomotion. Stimulating through chronically implanted nerve cuffs ensured a stable stimulation over time. The increase in reflex amplitude was well above the small increase in the amplitude of the locomotor bursts themselves that results from the denervation. Short latency responses (P1) were seen in flexor muscles, especially at the knee (semitendinosus) and ankle (tibialis anterior and extensor digitorum longus), with stimuli applied in the swing phase and also to a lesser degree in the later part of the cycle. Longer latency responses (P2) were increased in hip, knee, and ankle flexors, as well as in a contralateral extensor (vastus lateralis) ...

Nature communications, Jan 7, 2015

A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA p... more A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinatin...

Brain : a journal of neurology, Jan 8, 2017

Neurology, Jan 18, 2014

To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyeli... more To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the ...

Annals of Clinical and Translational Neurology, 2015

Objective: The objective of this study was to investigate the genetic etiology of the X-linked di... more Objective: The objective of this study was to investigate the genetic etiology of the X-linked disorder "Hypomyelination of Early Myelinating Structures" (HEMS). Methods: We included 16 patients from 10 families diagnosed with HEMS by brain MRI criteria. Exome sequencing was used to search for causal mutations. In silico analysis of effects of the mutations on splicing and RNA folding was performed. In vitro gene splicing was examined in RNA from patients' fibroblasts and an immortalized immature oligodendrocyte cell line after transfection with mutant minigene splicing constructs. Results: All patients had unusual hemizygous mutations of PLP1 located in exon 3B (one deletion, one missense and two silent), which is spliced out in isoform DM20, or in intron 3 (five mutations). The deletion led to truncation of PLP1, but not DM20. Four mutations were predicted to affect PLP1/DM20 alternative splicing by creating exonic splicing silencer motifs or new splice donor sites or by affecting the local RNA structure of the PLP1 splice donor site. Four deep intronic mutations were predicted to destabilize a long-distance interaction ª a These authors share first authorship. b These authors share senior authorship.

Neuropediatrics, 2015

Objective This study aims to ascertain frequency of mutations in POLR3A or POLR3B, which are asso... more Objective This study aims to ascertain frequency of mutations in POLR3A or POLR3B, which are associated with 4H leukodystrophy, in a cohort of patients with unclassified hypomyelination. Methods and Results In a cohort of 22 patients with the magnetic resonance imaging (MRI) diagnosis of unclassified hypomyelination and without typical clinical signs, we evaluated clinical and MRI features. Developmental delay or intellectual disability, ataxia, and spasticity were frequent symptoms. POLR3A and POLR3B were sequenced. A compound heterozygote mutation in POLR3B was found in only one patient. Additional investigations allowed a definitive diagnosis in 10 patients. Conclusion Mutations in POLR3A or POLR3B are rare in patients with unclassified hypomyelination, and alternative diagnoses should be considered first.

The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques

Background: The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations rep... more Background: The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability. Methods: Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin. Results: A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutation...

Movement disorders : official journal of the Movement Disorder Society, Jan 15, 2010